Derivatives of 1-phenoxy-3-amino-propan-2-ol

ABSTRACT

THE PRESENT INVENTION RELATES TO NEW PHARMACOLOGICALLY VALUABLE DERIVATIVES OF 1-PHENOXY-3-AMINO-PROPAN-2-OL HAVING THE FORMULA   (X-NH-CH2-CH(-OH)-CH2-O-)-BENZENE   AND THE ALDEHYDE CONDENSATION PRODUCTS AND ACID ADDITION SALTS THEREOF WHEREIN X IS SELECTED FROM THE GROUP CONSISTING OF   PYRIDYL-CO-CH=CH- AND PYRIDYL-CH(-OH)-CH2-CH2-   WHREIN THE PHENYL RING MAY HAVE ATTACHED TO IT UP TO THREE SIMILAR OR DIFFERENT SUBSTITUENTS SELECTED FROM THE GROUP CONSISTING OF ALKYL, ALKENYL, ALKINYL, CYCLOAKYL, CYCOALKYL, ALKOXY, ALKENYLOXY, ALKINYLOXY, PHENYL, HALOGEN AND -NR1R2, WHREIN R1 IS SELECTED FROM ALKYL AND ACYL, AND R 2 IS SELECTED FROM HYDROGEN AND ALKYL; AND TO THE PRODUCTION THREOF BY A METHOD SELECTED FROM (A) REACTING 1-PHENOXY-3-AMINO-PROPAN-2-OL HAVING THE FORULA   (NH2-CH(-OH)-CH2-O-)-BENZENE   WITH A COMPOUND HAVING THE FORMULA Y-X, WHEREIN X HAS THE ABOVE-DEFINED MEANIIN AND Y IS SELECTED FROM HALOGEN -OH,-OK OR-ONA; (B) RACTING A COMPOUND OF THE FORMULA   (Z-CH2-)-BENZENE   WITH A COMPOUND OF THE FORMULA H2N-X, WHEREIN X HAS THE ABOVE-DEFINED MEANING AND Z IS SELECTED FROM   OXIRANYL AND -CH2(-OH)-CH2-HALOGEN   (C) REACTING A PHENOL   PHENOL   WTH Z-CH2-NH-X, WHEREIN X AND Z HAVE THE MANING DEFINED ABOVE.

United States Patent Office 3,830,806 Patented Aug. 20, 1974 US. Cl. 260-240 J 11 Claims ABSTRACT OF THE DISCLOSURE The present invention relates to new pharmacologically valuable derivatives of l-phenoxy-3-amino-propan-2-ol having the formula and the aldehyde condensation products and acid addition salts thereof wherein X is selected from the group consisting of wherein the phenyl ring may have attached to it up to three similar or different substituents selected from the group consisting of alkyl, alkenyl, alkinyl, cycloalkyl, cycloalkenyl, alkoxy, alkenyloxy, alkinyloxy, phenyl, halogen and NR R wherein R is selected from alkyl and acyl, and R is selected from hydrogen and alkyl; and t the production thereof by a method selected from (A) reacting 1-phenoxy-3-amino-propan-2-ol having the forwith a compound having the formula Y-X, wherein X has the above-defined meaning and Y is selected from halogen, OH, --OK or --ONa; (B) reacting a compound of the formula with a compound of the formula H NX, wherein X has the above-defined meaning and Z is selected from and CHCH halogen;

(C) reacting a phenol with ZCH -NH--X, wherein X and Z have the meaning defined above.

The invention relates to new pharmacologically valuable derivatives of 1-phenoxy-3-amino-propan-2-ol of the general formula I together with their aldehyde condensation products and acid addition salts wherein X is and the phenyl ring I may have up to three similar or different substituents selected from alkyl, alkenyl, alkinyl, cycloalkyl, cycloalkenyl, alkoxy, alkenyloxy, alkinyloxy, phenyl, halogen or the radical --NR R R standing for alkyl or acyl R standing for hydrogen or alkyl.

Compounds according to the invention in which X signifies are preferred.

The pyridyl radicals in the compounds according to the invention can be 2-, 3- or 4-pyridyl radicals.

Within the framework of the present invention, the compounds of the general formula I are also understood to include possible stereo-isomers and optically active compounds and mixtures thereof, especially the racemates.

The substituents of the phenyl ring 'I possess in particular the following meanings:

Alkyl with 1 to 4 carbon atoms, e.g. methyl, ethyl, propyl,

tert.-butyl;

Alkenyl with up to 6 carbon atoms, preferably vinyl,

allyl, methallyl, crotyl;

Alkinyl with up to 6 carbon atoms, e.g. propargyl;

Cycloalkyl with a ring size of from 5 to 8 carbon atoms,

preferably cyclopentyl and cyclohexyl;

Cycloalkenyl with a ring size of from 5 to 8 carbon atoms,

preferably cyclopentenyl;

Alkoxy, alkenyloxy and alkinyloxy in each case with up to 5 carbon atoms, preferably methoxy, ethoxy, propoxy, butoxy, allyloxy, methallyloxy, propargyloxy;

Halogen, preferably bromine or chlorine.

Alkyl radicals for R or R preferably possess from 1 to 2 carbon atoms.

The acyl radical for R is understood to include the aryl-substituted or alkyl-substituted carbonyl radical with up to 11 carbon atoms derived from an aromatic or ali phatic carboxylic acid, e.g. formyl, acetyl, propionyl, butyryl, benzoyl, naphthoyl, phenyl acetyl, but preferably acetyl or benzoyl.

' The aldehyde condensation products of the compounds of the general formula I are oxazolidines of the formula Ic N X e I -OCH1 R3 which are formed during the condensation of compounds of the general formula I with an aldehyde of the formula:

R CHO in which R, signifies hydrogen or a lower alkyl radical with up to 4 carbon atoms.

Inorganic and organic acids are suitable for forming salts with the compounds of the general formula 1. Suitable acids, for example, are hydrochloric acid, hydrobromic acid, phosphoric, sulphuric, oxalic, lactic, tartaric,

3 acetic, salicylic, benzoic, citric or adipic acids. Pharmaceutically acceptable acid addition salts are preferred.

Compounds of the general formula I can be produced, for example, by the processes described below, in which the phenyl rings I of the following formulae diagrams can be substituted as stated above in the case of the general formula I.

PROCESS A A 1-phenoxy-3-amino-propan-2-ol of the general formula II is reacted with a compound of the general formula IH to form a compound according to the invention I:

In this, X has the meaning already given and Y signifies halogen, especially chlorine or bromine, and if X signifies -CH=CH-fi I it may also signify --OH, -OK or Na.

PROCESS B A compound of the general formula IV is reacted with a compound of the general formula V to give a compound according to the invention 1:

In this, X has the meaning already given above and Z signifies:

-cH--cn, a

Hal signifies a halogen 'atom, especially chlorine or promine.

PROCESS 0 Compounds of the general formula I according to the invention can also be synthesised by reacting a compound of the general formula VI with a phenol of the general formula VII.

VII VI Z and X have the meanings already given above.

Process D The preferred compounds Ib according to the invention X=-CHz-CHz-CHOH J! in formula I 4 can also be produced by the hydrogenation of the compounds Ia according to the invention, and also of compounds of the general formulae VIII, IX 01 X;

the reaction is accelerated by the addition of an acid, preferably hydrochloric acid.

When Y=OH, catalytic quantities of the acid, are already sufiicient, for example of acetic or formic acid. If Y: ONa or OK, then about 1 mole of the acid is added. Instead of this, it is also possible to use the compound of the general formula II in the form of a salt, for example of the hydrohalide. If Y signifies halogen, then the compound of the general formula III can also be used in the form of the hydrohalide. In the Process A, the acid addition salts of the compounds I may result.

The pyridiyl propenone compounds of the general formula 111a which are required as the initial compounds IIIa X=OH=OH-("J in Formula III vinylogous, 2-, 3- or 4-pyridinecarboxylic acids which can be produced in this way, it is possible by hydrolysis to produce the vinylogous pyridinecarboxylic acid (Y=OH in formulate 111a), which in turn can be converted with suitable halogenating agents, such as thionyl chlorides or phosphorus tribromide, into the corresponding vinylogous pyridinecarboxylic acid halides of the general formula IIIb (Hal-halogen, especially C1 or Br).

Compounds of the general formula III, in which Y=halogen (Hal), especially bromine or chlorine, and

X-CHa-CHz-CHOH I \N/ and to which the general formula IIIc applies:

Hal-CHr-CHr-CH I can be produced from the corresponding compounds IIIb by hydrogenation, advantageously with complex hydrides, such as lithium aluminium hydride, sodium boron hydride or the like.

The compounds of the general formula II required as initial compounds can be produced by reacting a compound of the general formula IVa or IVb:

mula VII:

with an epihalogenhydrin, advantageously with epichlorohydrin or epibromohydrin. According to the particular reaction conditions, when this is done one obtains a compound of the general formula IVa or IVb or a mixture of compounds of the general formulae IVa and IVb. The resultant reaction product can be isolated for its further reaction with ammonia, but it can also be further reacted direct without isolation.

When carrying out the process B, it is also possible to use a mixture of two compounds IVa and IVb which are similarly substituted in the phenyl ring I. Thus one obtains direct by the reaction of 3-amino-1-(pyridyl)-propan-l-ols of the formula Vb with compounds of the gen- VII eral formulae IVa or IVb compounds according to the invention of the general formula Ib:

IVa

The reactions according to the process B are carried out in a suitable solvent at normal or elevated temperature. Suitable solvents are, for example, benzene, toluene, acetone, dioxane, alcohols. The reaction of compounds of the general formula IVb can be carried out in the presence of acid-binding agents, such as potash, soda etc. or without acid-binding agents, when in the latter case one usually obtains the hydrohalides of 1b.

In the process C one can also use instead of a uniform compound of the general formula VI a mixture, for example of VIa and VIb:

CHr-CH-NH-CHr-C Hz-CH I O OH VIa

HaF-CHr-CH-NH-CHrCHr-CH I H (an in each case with the same pyridyl radical. The reactions according to Process C can be carried out either in an aqueous alkaline solution, for example in dilute caustic soda, or in suitable solvents, such as benzene, toluene, dioxane, but preferably in absolute acetone in the presence of potash or soda. The reaction can be carried out at normal temperature or can be accelerated or brought to termination by heating.

According to the process D it is possible to produce from the compounds Ia according to the invention:

OH O

by hydrogenation compounds according to the invention For hydrogenation one advantageously uses complex hydrides, such as lithium aluminium hydride, sodium boron hydride and the like. The reaction is carried out under the reaction conditions known for these hydrides, normally in an alcohol/water mixture at room temperature or elevated temperature, for example boiling under a reflux. The hydrogenation can also be carried out catalytically, for example using a palladium/carbon catalyst.

Analogously it is possible for compounds of the general formulae VIII, IX and X to be hydrogenated. Initial compounds of the formula VIII can be obtained by reacting a compound of the general formula XI with a compound of the general formula IIIb or 1110.

When written in general terms, the equation of the reaction reads as follows: 1

NH-X VIII in which in the general formula IIId Hal signifies halogen,

preferably chlorine. The reactions between the compounds For the production of compounds of the general formula XI one reacts, for example, a phenol of the general formula VII with a halogen acetone of the general formula XII, for example bromoacetone, one brominates or chlorinates the resultant product of the general formula XIII, as a result of which one obtains a compound of the general formula XIV, which is converted with ammonia or compounds which split off ammonia into a compound of the general formula X1.

Initial compounds of the general formula IX can be produced by a Mannich Reaction from a compound of the general formula XI, formaldehyde and 2-, 3- or 4-acetylpyridine.

Compounds of the general formula X can be synthesized by a Mannich Reaction from a compound of the general formula II, formaldehyde XV and a 2-, 3- or 4- acetylpyridine of the general formula XVI:

Aldehyde condensation products of the formula Ic of the compounds according to the invention are obtained if one reacts compounds of the general formula I with an aldehyde of the formula R --CHO, in which R signifies hydrogen or a lower alkyl radical, in a diluent or solvent, for example ethyl alcohol, preferably in the presence of an acid catalyst, for example acetic acid or hydrochloric acid and preferably at elevated temperature. The water formed during the reaction can be removed by means of an entraining agent, for example benzene, by azetropic distillation or by means of a dehydrating agent such as anhydrous potassium carbonate.

The acid addition salts of the compounds of the general formula I can be produced in a known manner from the components. When this is done it is generally advantageous to use a diluent, and in the case of an excess of acid one generally obtains the di-salts of the compounds of the general formula I. The mono-acid-addition salts are obtained either by the deliberate addition of only 1 mole of acid or by the partial hydrolysis of the di-acid-addition salts.

From the racemates there may be obtained in the manner known per se the compounds optically active by racemate-cleavage with the aid of optically active acids.

Suitable optically-active acids are, for example:

'+ Mandelic acid Tartaric acid Dibenzoyl-tartaric acid Di-p-toluyl-tartaric acid 1 Campharic acid When reacting the racemate with an optically active acid, salts are formed which differ both with regard to their optical and their physical properties, e.g., with respect to their solubilities and melting points and by this they may be separated by fractional crystallisation. From the salts thus separated the optically active compounds of the general formula I may be set free with the aid of bases, such as potassium or sodium hydroxide.

The compounds according to the invention of the general formula I, their aldehyde condensation products Ic and their pharmaceutically acceptable acid addition salts possess valuable pharmaceutical properties. The com pounds of the general formula Ia exert actions on the central nervous system and possess anorectic properties. As already mentioned, they are further valuable intermediates for the manufacture of compounds of the general formula Ib. The compounds of the general formula Ib are suitable for the treatment or prophylaxis of cardiac diseases, especially of the angina pectoris and different forms of cardiac arrhythmias.

The compounds according to the invention can therefore be used either alone, or mixed with one another or mixed with pharmaceutically unobjectionable diluents or supports as pharmaceutical preparations. The pharmaceutical preparations can occur in the form, for example, of tablets, capsules, aqueous or oily solutions or suspensions, emulsions, injectable aqueous or oily solutions or suspensions, dispersable powders or aerosol mixtures. The pharmaceutical preparations can, besides the compounds of the general formula I according to the invention, also contain one or more other pharmaceutically effective substances, for example tranquillisers, such as Luminal, Meprobamate and Chlorpomazine; vasodilators, such as for example glycerine trinitrate and carbochromen; diuretics, such as for example chlorothiazide; heart-toning agents such as for example digitalis preparations; hypotensives, such as for example rauwolfia alkaloids; broncho-dilators and sympathomimetic agents such as for example isoprenaline and ephedrine.

.A tablet containing one of the compounds of the present invention may be, for example, of the following composition:

1 (fi pyridyl)-3-[3-(o-ethoxy-phenoxy)-2-hydroxypropylamino]-propano1-optically active and laevorotatory 5 Aerosil 5 Cornstarch DAB 7 20 Lactose DAB 7 30 Avicel M.F. XIII 24 Collidone 25 I 4 Magnesium stearate USP XVIII 2 According to the seriousness of the case to be treated, e.g., 1 to 2 of the tablets may be dispensed to a patient three times a day.

The substances of the present invention were tested with regard to their blocking action on the fl-receptors as follows Method quency response. The first derivation of the left ventricular pressure =Dp/dt in terms of mm. Hg/sec.) was derived electronically from the pressure signal. All measurements were continuously recorded with a BRUSH Mark 260 recorder.

Experimental procedures Three doses of isoproterenol (0.l-0.2-0.5 gamma/kg.) were injected intravenously. Thereafter increasing doses of the test compound were given intravenously, each dose followed always by the injection of isoproterenol about 10 minutes after application. The Beta-blocking action of the test compound was considered to be maximal if the stimulating effect of 0.5 gamma/kg. isoproterenol intravenously on Dp/dt max. was neary completely inhibited. The different doses used were added up and this dose was taken to compare the effectiveness of the different compounds on resting Dp/a't max.

The following tablet gives the results of the pharmacological tests described above.

Changes induced by the Dose comadded pound 1 Dr l mg.lkg., max., Compound i.v. percent l-[B-pyridyl]-3-[3-(0-allyloxy-phenoxy)-2- hydroxypropylamino]-propanol-1 0. 4 1-{fl-pyridyl]-3-[3-(o-ethoxyphenoxy)-2- hydroxyropylaminfl-propanol-l 0.4 :H) l-Ifl-pyndyfl-Zi- 3-(m-methylpheno y) hydroxyro ylarnino1-propanol-1 0.9 -11 l-[B-pyrrdy -3- 3-(p-1nethoxyphenoxy)-2- hydroxy-pro ylamino1-propauol-l 0.9 +79 I-IB-pyridyl -3- 3-(o-phenylphenoxy)-2- hydrqxyr0 ylarmno1-propanol-1. 0.9 22 1-[fi-pyridyl -3 3-(p-tert.-butylpheno hydroxyr0 ylamino1-propanol-l 0.85 22 l-lfl-pyridyl -3- 3-(o-chlorophenoxy)-2- hydroxy-propylaminolpropanol-l 0. 9 +220 I-[fl-pyridyl -3- 8-(m-methoxyphenoxy)-2- hydroxyr0 ylamino1-propanol-1 0.9 +30 l-IB-pyrrdyl -3- fl-(o-allylphenoxy)-2-hydroxyropylamnol-propanol-l 0. 9 20 1- -pyridyl ii-l3-(p-butoxyphenoxy)-2- hydroxyro ylaminol-propanol-l 0.9 +22 l-lfi-pyridyl -3- 3-(o-ethoxyphenoxy)-2-hydroxyropylamnoLpropanol-l (laevorotatory) 0.19 8 1- -pyndyl -3 [3-(o-eyclopentylphenoxy)-2- hydroxy-propy1amino1-propanol-l 0. 6 19 Propanolol (comparative compound) 0. 9 ---41 The compounds on test were employed in the form of their hydrochlorides.

The production of the compounds according to the invention is explained in greater detail on the basis of the following examples. The compounds according to the invention are frequently non-distillable oils, so that in some cases no melting point is given. In all cases, however, the structure stated is confirmed by the molecular analysis and/or the infrared or nuclear resonance spectrum.

Example l.4.2 g. of l-amino-3-(o-allyloxyphenoxy)- propan-Z-ol hydrochloride are suspended in 33 mls. of alcohol and then 2.8 g. of the sodium salt of nicotinoyl vinyl alcohol are added and the mixture stirred at room temperature for 20 hours. The suspension is filtered at the pump and the residue washed with alcohol. The filtrate together with the washing alcohol is concentrated in vacuo. There remains an oil which becomes solid after a short time. The residue is processed several times with water and then re- 1 1 crystallised from alcohol. In this way one obtains l-nocotinoylvinylamino-3-(o-allyloxyphenoxy)-propan-2-ol.

OH OOHzCH=CHz N M.p.: 98 C. Analysis (CHI-122N204):

calculated: C, 67.8; H, 6.2; N, 7.9. found: C, 67.7; H, 6.4;N, 8.1. Yield: 4.6 g.-=81% of theory.

The requisite sodium salt of nicotinoyl vinyl alcohol can be produced as follows:

47 g. of sodium methylate are suspended in 340 mls. of absolute benzene, and then whilst stirring at 10 C. a mixture of 74 g. of ethyl formate and 100 g. of 3-acetylpyridine is added slowly drop by drop and the mixture is then left for 24 hours at room temperature. It is then filtered at the pump, washed twice with absolute benzene, then twice with absolute alcohol and finally twice with ether. In this way one obtains the sodium salt of nicotinoyl vinyl alcohol with a yield of 90% of theory.

If instead of the 3-acetylpyridine one takes 2-acetylpyridine or 4-acetylpyridine, during the reaction with ethylformate and sodium methylate one obtains in an entirely analogous manner the sodium salts of the vinylogous pyridine-Z- or -4-carboxylic acid.

The requisite 1-amino-3- (o-allyloxyphenoxy) -propan-2- 01 can be produced as follows:

60 g. of l-(o-allyloxypheuoxy)-2,3-epoxy-propane (produced from o-allyloxyphenol and epichlorhydrin in the presence of potash in acetone) are dissolved in 600 mls. of methanol, 300 mls. of liquid ammonia are added and it is stirred for 3 hours in the autoclave at 70 C. It is then concentrated, the residue is dissolved in benzene, extracted twice with dilute hydrochloric acid, the aqueous acid phase is separated, rendered alkaline, extracted three times with benzene and combined benzene phases are concentrated. The solid residue is re-crystallised once from benzene. In this way one obtains l-amino-3-(o-allyloxyphenoxy) -propan-2-ol:

OCH(l)HCH2-NH2 O-CH2CH=CH2 in a yield of 67% of theory. M.p.: 89 C.

The base can be converted in the usual manner with an ether solution of hydrochloric acid into 1-amino-3-(oallyloxyphenoxy) propan 2 ol hydrochloride with a melting point of 110 C.

Example 2.4.6 g. of l-nicotinoyl vinylamino-3- (o-allyloxyphenoxy)-propan-2-ol are dissolved in 45 mls. of methanol and 12 mls. of water, 2.5 g. of sodium boron hydride are added and the mixture is stirred at room temperature for 5 hours. Then it is stirred for 8 hours at 70 C. Whilst adding a further 8 g. of sodium boron hydride in portions, then the mixture is concentrated in vacuo and the residue is taken up in 60 mls. of water and 60 mls. of chloroform, the chloroform phase is separated, the aqueous solution is extracted a further twice with chloroform, the chloroform solution is dried with sodium sulphate and concentrated in vacuo.

The residual oil is dissolved in dilute hydrochloric acid, the solution is extracted three times with benzene and then the acid aqueous phase is rendered alkaline with soda, and finally extracted three times with chloroform. The chloroform solution is washed with water, dried and concentrated in vacuo.

In this way one obtains 1-(3'-fl-pyridyl-3'-hydroxypropylamino) 3 (o allyloxyphenoxy) propan 2 01 as a thick yellow oil.

Analysis: (C20H26N2O4):

calculated: C, 67.0; H, 7.3; N, 7.8; O, 17.9. found: C, 67.2; H, 7.1; N, 7.6; O, 17.8. Yield: 3.9 g.=82% of theory.

Example 3.6.8 g. of l-nicotinoyl vinylamino-3- (o-ethoxyphenoxy) -propan-2-ol H OLNI are dissolved in 40 mls. of methanol and 10 mls. of water, 3.9 g. of sodium boron hydride are added and the mixture is stirred at room temperature for 10 hours. Then it is stirred for 6 hours at 70 C. with the addition of a further 5 g. of sodium boron hydride in portions, then the mixture is concentrated in vacuo and the residue taken up in 50 mls. of chloroform and 50 mls. of water, the chloroform phase is separated, the aqueous phase is extracted a further twice with chloroform, then the combined chloroform extracts are dried and concentrated in vacuo. The residual oil is converted into the oxalate and the salt is re-crystallised from alcohol/ether.

In this way one obtains 1-(3'-fl-pyridyl-3'-hydroxypropylamino)-3-(o-ethoxyphenoxy)-propan-2-ol dioxalate. M.p.: 133 C. decomposed Analysis: (C23H30N2012):

calculated: C, 52.5; H, 5.7; N, 5.3. found: C, 52.6; H, 5.9; N, 5.5. Yield: 9 g.=86% of theory.

Example 4 3.4 g. of l-nicotinoyl ethylamino-3-(o-ethoxyphenoxy)- propan-Z-ol, prepared from 3-acetylpyridine, 1-amino-3- o-ethoxyphenoxy) -propan-2-o1 and formaldehyde according to Mannich are dissolved in 15 mls. of methanol and 15 mls. of water and then; whilst stirring at room temperature, in all 2 g. of sodium boron hydride are mixed with it in portions over a period of 3 hours, and then the mixture is left to stand at room temperature for 24 hours. The solution is concentrated, taken up in chloroform/water and the chloroform solution processed. In this way one obtains 1-(3'- 3-pyridyl-3'-hydroxypropylamino) -3- (o-ethoxyphenoxy) -propau-2-ol:

QOOHr-CH-CHn-NH-OHz-CHr-CH- in a yield of 78% of theory.

Example 5.--4.4 g. of 1-amin0-3-(p.-tert.-butylphenoxy)- propan-2-ol:

are dissolved in 80 mls. of ethyl acetate and 5.6 g. of anhydrous potash are added. To thismixture one slowly 7 13' adds whilst cooling and stirring a mixture of 4.1 g. of nicotinoylvinylchloride hydrochloride:

(prepared from the sodium salt of nicotinoyl vinyl alcohol, which first of all is converted with HCl gas into the hydrochloride of the free nicotinoyl vinyl alcohol and then with thionyl chloride into the vinylogous nicotinic acid chloride hydrochloride) in 50 mls. of ethyl acetate and is then stirred for a further 24 hours at room temperature. Then it is filtered at the pump, the residue taken up in water, rendered alkaline with sodium bicarbonate and the solution extracted again with ethyl acetate. The

ethyl acetate extracts are concentrated in vacuo together with the original ethyl acetate filtrate. After re-crystallising several times from toluene one obtains in this way 1-nicotinoyl-vinylamino-3-(p tert.-butylphenoxy)-propan- 2-01.

CH-CHa-NHCHz-CHa-CH (M.p. of the dioxalate 176 C.). Example 6.11.4 g. of the sodium salt of vinologous pyridin-4-carboxylic acid CCH=GH0N&

are agitated for 24 hours at room temperature with 16.5 g. of 1-amino-3-(o-ethoxyphenoxy)-propan-2-ol hydroin 120 mls. of ethanol. It is filtered at the pump, the residue is washed with ethanol and then the ethanol filtrates are concentrated in vacuo. An oil is left which becomes solid after several hours. The product is washed several times with water and then re-crystallised from methanol/water. In this way one obtains l-(isonicotinoylvinylamino-3-(o-ethoxyphenoxy)-propan-2-ol:

0-CHr-CH-C Hz-NH-CH= 011-? $11 -CzH 14' M.p. 69 C. Analysis: (C19H32N2O4):

calculated: C,66.'6; H, 6.4; N, 6.4; N, 8.2. found: C, 66.3; H, 6.6; N, 7.9. Yield: 15 g.-=66% of theory.

Example 7 14.5 g. of 1-(isonicotinoylvinylamino) 3 (o-ethoxyphenoxy)propan-2-ol are dissolved in mls. of methanol, and then 32 mls. of water are added and 8.1 g. of sodium boron hydride are mixed with the solution in portions. Then it is agitated at room temperature of 6 hours and then a further 8.1 g. of sodium boron hydride are added and the mixture is heated at 70 C. for 6 hours. It is then concentrated in vacuo, the residue is dissolved in 40 mls. of chloroform and 40 mls. of water, the chloroform phase is separated and the aqueous phase is extracted once again with chloroform. The combined chloroform extracts are dried and concentrated in vacuo. The residual oil is dissolved in dilute hydrochloric acid, the solution is washed twice with benzene, the aqueous solution is adjusted to alkalinity with sodium bicarbonate, extracted with chloroform and the chloroform solution is concentrated in vacuo. The residual oil is dissolved in ethyl acetate and converted into the oxalate with an alcoholic oxalic acid solution. The salt which is greasy at the beginning becomes solid when heated with ethyl alcohol. After the conversion of the oxalate into the free base one obtains in this way 1-(3--y-pyridyl-3-hydroxypropylamino)-3-(o-ethoxyphenoxy)-propan-2-ol:

as a crystalline product.

M.p.: 92 C. Analysis: (C H N O calculated: C, 65.9; H, 7.5; N, 8.1. found: C, 65.6; H, 7.5; N, 8.1. Yield: 9.9 g. :67% of theory.

The same product is obtained if one reacts 1-amino-3- (o-ethoxyphenoxy)-propan-2-ol:

with 1-('y-pyridyl)-3-chloropropan-1-ol ol-cm-cm-on (prepared by reducing isonicotinoylvinyl chloride) in absolute acetone and anhydrous potash.

Example 8.4.4 g. of 1-(2-methoxy-4'-allylphenoxy)- 2,3-epoxypropane OH CHCH: O-GHa-CH-CH;

(prepared by heating eugenol with epichlorohydrin and potash in anhydrous benzene: B.P. M 138-145 C.) are heated for 8 hours under a reflux with 6 g. of l-(flpyridyl) -3-aminopropan-1-ol:

HgNCHr-CH:(|3H OH in 60 mls. of alcohol. It is then concentrated in vacuo.

in 60 mls. of alcohol. It is then concentrated in vacuo, the residue is dissolved in dilute hydrochloric acid, the solution is washedseveral times with benzene, adjusted to an alkaline pH with soda, and the alkaline solution is extracted with chloroform. The chloroform extracts are concentrated in vacuo, the residue is dissolved -in a small quantity of absolute dioxane, an insoluble portion is filtered off and the filtrate is mixed with an ether solution of oxalic acid. A precipitate is formed which is first of all greasy but which becomes solid when heated with absolute ethyl alcohol. The product is recrystallised several times from absolute ethyl alcohol. On this way one obtains 1-(3-/3-pyridyl 3 hydroxypropylamino)-3- (2-methoxy-4'-allylphenoxy)-propan-2-ol dioxalate. M.P.: 132 (decomp.) Analysis: (C25'H32N2O12):

calculated: C, 54.3; H, 5.8; N, 5.1. found: C, 54.1; H, 6.0; N, 4.8.

Yield: 4.8 g.=43% of theory.

The l-(fl-pyridyl)-3-aminopropan-l-ol required as the initial product can be prepared as follows:

16 manner to the instructions contained in Example 2 and in this way one obtains a 55% yield of 1-(p-pyridyl)-3- benzylaminopropanl-ol as an oily product, which can be debenzylated in the usual manner with hydrogen in the autoclave to givel-( fipyridyl)-aminopropan-1-ol on-om-onl-un,

N N the sodium salt of mcotmoyl vinyl alcohol, 1s reacte correspondingly, signifies a 3 py,ridy1radica1 and with ben-zylannne hydrochloride analogously to the 1n- Py a 4 pyridyl radicaL l cqmamed P the resultant In the Table below, compounds of the general formula: (nicotmoylvmyl)-benzylam1ne:

O-CH2-CH-CHz-NH-X CCH=CHNH-CH2- H OH 0 on 5 are listed, in which (R0,, and X possess the meanings is reduced with sodium boron hydride in an analogous showninthe Table.

TABLE I 3-CH5 cH=oH-0oa-Py on, will not-distil. 3-CH3 -CH2CHz-CHOH3-Py Dlxalate, l)VI.P. 156 0.

660111 2-cyclopentyl -CH=CHG 0-3-Py M.P. C. 2-cyelopentyl -CHzCHr-CHOH3-Py Dioxalate, M.P. 166 C.

' (decomp.). 2-C6H5 CH=CHC03-Py .P. 105 0. 2"C6H5 -CH CH -CH0H3-Py Dixalate, 1;J.P. 151 0.

-' ecom 4-CH3C0--NH- -CH=CHCO3-Py M.P. 107 o. (decomp.). 4-CH CO-NH- -GH -CHg-CH0H3-Py on, will not distil. 2,6-012 -CH=GHC0-3-Py M.P. 127 0. 2,6-C1a --CHzCH2CHOH-3-Py Dioxalate, M.P. 0.

'- (decomp.). 2-OC2H5 CH=CHCO3-Py M.P. 92 0. 4-0 CH3 -CH=OH-OO3-Py M.P. 108 0. 4-0 CH3 -CHrCHzCHOH3-Py Dioxalate, My. 139 0. Z-OCHz, 4-CHz-CH=CH CH=OHOO'-3-Py M.P. 94 0, 2-OG2H5 -CH=OHCO2-Py M.P. 88 0, 2-OCzH5 --CH -CHz--CH-2-Py on.

zonmo CH=CHCO-4-Py 011. 94011930 --CH -OH -CH4-Py v Dioxalate,M.P.142 o..

Z-O-CHz-C CH -OH=QHCO-2-Py 0n. 2-OCHZ'CECH --CHzCH- CH2-Py on.

Z-eyelohexyl CH=CH-CO4-Py M.P. 103 C.

2-cyelohexyl -CHzCHzCH-4-Py Dloxalate, M.P. 161 C.

3-N(CHa): CH=C H-CO4-Py on.

3-N(CH3)2 -CHz-GH (i7H-4-Py Oil.

2-01 --CH=CHCO--3-Py M.P. 126 0.

2-o1 -CH CHzCH-3-Py M.P. 96 0.

1. Derivative of l-phenoxy 3 aminopropane 2 ol having the formula @o-om-cH-cm-Nm-x and CHzCH:- CH

and wherein the phenyl ring I may have up to three similar or difierent substituents selected from alkyl having l-4 carbon atoms, alkenyl and alkinyl having in either ease up to 6 carbon atoms, cycloalkyl and cycloal lt'hyl having in either case a ring size of -8 carbon atoins, alkoxy, alkenyloxy and alkinyloxy having in either case up to 5 carbon atoms, phenyl, chlorine, bromine and the radical NR R wherein R is selected from alkyl haying 1- 4 carbon atoms and alkanoyl having up to 11 carbon atoms and benzoyl, haphthoyl and phenyl acetyl and R is selected from hydrogen and alkyl having 'up to 4 carbon atoms.

2. Derivative of l-phenoxy 3 aminopropane 2 01 having the formula and pharmaceutically acceptable acid addition salts thereof, wherein X is selected from the group consisting of alkenyloxy and alkinyloxy having up to 5 carbon atoms" in each case, phenyl, chlorine and bromine and the radical N R :R in which R, is selected from the group consisting of alkyl having 1-4 carbon atoms andalkaiioyl having up to 11 carbon atoms and benzoyl, naphthoyl and phenyl acetic, and R is a substituent selected froih the group consisting of hydrogen and alkyl having up to 4 carbon atoms.

' 3. Derivative of 1-phenoxy-3 aminopropane 2 01, according to Claim 1, wherein the phenyl ring I is substituted by a substituent selected from the group consisting of vinyl, allyl, methallyl and crotyl.

' 4. Derivative of l-phenoxy 3 aminopropane 4 2 01, according to Claim 1, wherein the phenyl ring I is substituted by cyclopentenyl.

5. Derivative of l-phenoxy 3 aminopropane 2 01 according to Claim 1, wherein the phenyl ring I is substituted by a substituent selected from the group consisting of cyclopentyl and cyclohexyl.

6. Derivative of l-phenoxy 3 aminopropane 2 01, according to Claim 1, wherein the phenyl ring I is substituted by a substituent selected from the group consisting of methoxy, ethoxy, propoxy, butoxy, allyloxy, methallyl oxy, and propar'gyloxy.

7. Derivative of 1-phenoxy-3 aminopropane 2 01 according to Claim 1, wherein the phenyl ring I is substituted with the radical -NR R in which R is a substituent selected from the group consisting of methyl,

- ethyl, acetyl and benzoyl, and R is a stubstituent selected from the group consisting of methyl and ethyl.

8. Derivative of l-phenoxy 3 aminopropane 2 01, according to "Claim 2, wherein the phenyl ring is substituted by a substituent selected from the group consisting of vinyl, allyl, methallyl and crotyl.

9. Derivative of l-phenoxy 3 aminopropane 2 01, according to Claim 2, wherein the phenoyl ring I is substituted by a substituent selected from the group consisting of cyclopentyl and cyclohexyl.

10. Derivative of l-phenoxy 3 aminopropane 2 Q1, according to Claim 2, wherein the phenyl ring I is substituted with a subs-tituent selected from the group consisting of methoxy, ethoxy, propoxy, butoxy, allyloxy,

methallyloxy and propargyloxy.

1'1. Derivative of l-phenoxy-S-aminopropane 2 01, according to Claim 2', wherein the phenyl ring I is substituted by the radical -NR \R wherein R is a substitentselec'ted from the group consisting of methyl, ethyl, acetyl and benzoyl, and R is a substituent selected from the group consisting of hydrogen, methyl and ethyl.

Ross et al. 260296 AE o. THOMAS TODD, Primary Emmet US. Cl. X.R.

"260295 Rj 295 AM, 295.5 R, 295.5 A, 296 AB, 307 F; .424263 Y 

